How cancer cells communicate at long range in vivo?

Topics overview: How cancer cells communicate at long range in vivo, Aberrant DNA Methylation in Colorectal Cancer, JARID1 Histone Demethylases, How To Fine-Tune Cancer Immunotherapy, Methods and Applications of CRISPR-Mediated Base Editing.

1. Imaging Tunneling Membrane Tubes Elucidates Cell Communication in Tumors

Intercellular communication is a vital yet underdeveloped aspect of cancer pathobiology. This Opinion article reviews the importance and challenges of microscopic imaging of tunneling nanotubes (TNTs) in the complex tumor microenvironment. The use of advanced microscopy to characterize TNTs in vitro and ex vivo, and related extensions called tumor microtubes (TMs) reported in gliomas in vivo, has propelled this field forward. This topic is important because the identification of TNTs and TMs fills the gap in our knowledge of how cancer cells communicate at long range in vivo, inducing intratumor heterogeneity and resistance to treatment. Here Emil Lou at University of Minnesota in Minneapolis, USA and his colleagues discuss the concept that TNTs/TMs fill an important niche in the ever-changing microenvironment and the role of advanced microscopic imaging to elucidate that niche.

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2. Aberrant DNA Methylation in Colorectal Cancer: What Should We Target?

Colorectal cancers (CRCs) are characterized by global hypomethylation and promoter-specific DNA methylation. A subset of CRCs with extensive and co-ordinate patterns of promoter methylation has also been identified, termed the CpG-island methylator phenotype. Some genes methylated in CRC are established tumor suppressors; however, for the majority, direct roles in disease initiation or progression have not been established. Herein, Janson W.T. Tse at Olivia Newton-John Cancer Research Institute in Melbourne, Australia and his colleagues examine functional evidence of specific methylated genes contributing to CRC pathogenesis, focusing on components of commonly deregulated signaling pathways. They also review current knowledge of the mechanisms underpinning promoter methylation in CRC, including genetic events, altered transcription factor binding, and DNA damage. Finally, they summarize clinical trials of DNA methyltransferase inhibitors in CRC, and propose strategies for enhancing their efficacy.

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3. JARID1 Histone Demethylases: Emerging Targets in Cancer

JARID1 proteins are histone demethylases that both regulate normal cell fates during development and contribute to the epigenetic plasticity that underlies malignant transformation. This H3K4 demethylase family participates in multiple repressive transcriptional complexes at promoters and has broader regulatory effects on chromatin that remain ill-defined. There is growing understanding of the oncogenic and tumor suppressive functions of JARID1 proteins, which are contingent on cell context and the protein isoform. Their contributions to stem cell-like dedifferentiation, tumor aggressiveness, and therapy resistance in cancer have sustained interest in the development of JARID1 inhibitors. Here Kayla M. Harmeyer at University of Pennsylvania in Philadelphia, USA and her colleagues review the diverse and context-specific functions of the JARID1 proteins that may impact the utilization of emerging targeted inhibitors of this histone demethylase family in cancer therapy.

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4. Learning from the Proteasome: How To Fine-Tune Cancer Immunotherapy

Cancer immunotherapy has recently emerged as a forefront strategy to fight cancer. Key players in antitumor responses are CD8+ cytolytic T lymphocytes (CTLs) that can detect tumor cells that carry antigens, in other words, small peptides bound to surface major histocompatibility complex (MHC) class I molecules. The success and safety of cancer immunotherapy strategies depends on the nature of the antigens recognized by the targeted T cells, their strict tumor specificity, and whether tumors and antigen-presenting cells can efficiently process the peptide. Nathalie Vigneron at Ludwig Institute for Cancer Research in Brussels, Belgium and her colleagues review here the nature of the tumor antigens and their potential for the development of immunotherapeutic strategies. They also discuss the importance of proteasome in the production of these peptides in the context of immunotherapy and therapeutic cancer vaccines.

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5. Methods and Applications of CRISPR-Mediated Base Editing in Eukaryotic Genomes

The past several years have seen an explosion in development of applications for the CRISPR-Cas9 system, from efficient genome editing, to high-throughput screening, to recruitment of a range of DNA and chromatin-modifying enzymes. While homology-directed repair (HDR) coupled with Cas9 nuclease cleavage has been used with great success to repair and re-write genomes, recently developed base-editing systems present a useful orthogonal strategy to engineer nucleotide substitutions. Base editing relies on recruitment of cytidine deaminases to introduce changes (rather than double-stranded breaks and donor templates) and offers potential improvements in efficiency while limiting damage and simplifying the delivery of editing machinery. At the same time, these systems enable novel mutagenesis strategies to introduce sequence diversity for engineering and discovery. Here, Michael C. Bassik at Stanford University in Stanford, USA and his colleagues review the different base-editing platforms, including their deaminase recruitment strategies and editing outcomes, and compare them to other CRISPR genome-editing technologies. Additionally, they discuss how these systems have been applied in therapeutic, engineering, and research settings. Lastly, they explore future directions of this emerging technology.

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